Exploration of Novel <i>C</i>-Glucoside Formation and Application for SGLT2 Inhibitors —Discovery of Canagliflozin as a SGLT2 Inhibitor—

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  • Sakamaki Shigeki
    Research Unit/Nephrological & Endocrinological Science, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation
  • Kawanishi Eiji
    Research Unit/Frontier Therapeutic Sciences, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation
  • Nomura Sumihiro
    Research Unit/Nephrological & Endocrinological Science, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation

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  • 新規<i>C</i>-グルコシド合成法の開発とSGLT2阻害薬への応用—SGLT2阻害薬カナグリフロジンの創製—
  • 新規C-グルコシド合成法の開発とSGLT2阻害薬への応用 : SGLT2阻害薬カナグリフロジンの創製
  • シンキ C-グルコシド ゴウセイホウ ノ カイハツ ト SGLT2 ソガイヤク エ ノ オウヨウ : SGLT2 ソガイヤク カナグリフロジン ノ ソウセイ

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<p>Inhibition of sodium glucose co-transporter 2 (SGLT2) in vivo increases urinary glucose excretion (UGE) and controls blood glucose levels in hyperglycemic animals. T-1095 is the first orally active SGLT2 inhibitor, and it was discovered by optimizing the natural glucosyl product phlorizin. We focused on aryl-C-glucosides and optimized the analogs, resulting in the discovery of canagliflozin, which is metabolically more stable than T-1095. Canagliflozin markedly induced UGE compared with that of T-1095 because of its excellent pharmacokinetic properties in vivo and its high potency for inhibiting SGLT2. Canagliflozin was selected as a clinical candidate for treating type 2 diabetes mellitus and was approved in the USA and EU in 2013 and in Japan in 2014. In this study, we describe the synthesis of new C-glucoside analogs using a palladium-catalyzed cross-coupling reaction of glucal boronate and its application as an SGLT2 inhibitor.</p>

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